There is progressive attenuation of the effects of nitrates within the first 24 hours of continuous exposure. In a review of a transdermal nitrate system, the short duration of action of the formulation was ascribed to tolerance (64).
At first it was thought that tolerance was due to depletion of intracellular endothelial sulfhydryl groups (65), which are necessary for the biotransformation of organic nitrates to nitric oxide. It seems likely that tolerance occurs through several mechanisms, and the precise mechanisms are still uncertain (66). However, one possible mechanism of tolerance has been elucidated (67). Organic nitrates are converted to S-nitrosothiols when combined with sulfhydryl moieties in smooth muscles. These compounds activate guanylate cyclase, leading to an increase in the intracellular concentration of cyclic GMP, with resultant vascular relaxation and vasodilatation. As the supply of sulfhydryl within the smooth muscles is limited, prolonged exposure to organic nitrates results in its depletion and hence tolerance (68). Other mechanisms of nitrate tolerance that have been proposed include neurohumoral adaptation and a plasma volume-dependent mechanism (69). A unifying hypothesis, involving the excess production of superoxide anions, has been proposed (70).
In an assessment of how nitrate tolerance might be avoided, the efficacy of thrice-daily buccal glyceryl trini-trate and that of four times a day oral isosorbide dinitrate were compared (71); over 2 weeks, prolonged antianginal efficacy was maintained only with thrice-daily buccal administration. Nevertheless, in another study, transdermal glyceryl trinitrate seemed to offer a prolonged effect, sufficient to wean patients with unstable angina from intravenous nitrate therapy (71).
It has been convincingly shown that a nitrate-free period reduces nitrate tolerance (72). The modern strategy is to have a nitrate-free period when the patient is asleep, although this results in reduced protection from ischemia in the early morning, the time when many episodes of silent ischemia and myocardial infarction occur. Reports that ACE inhibitors (73) or carvedilol (74) reduce nitrate tolerance are as yet unconfirmed (75).
Three published controlled trials of the use of vitamin C in treating nitrate tolerance in 77 subjects overall have been reviewed (76). Vitamin C (3-6 g/day orally or by intravenous infusion) reduced nitrate tolerance for up to 3 days, without causing adverse reactions. However, before making definitive recommendations, studies of longer duration should be done in a larger number of patients.
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